Next Article in Journal
Genetic and Neuroimaging Approaches to Understanding Post-Traumatic Stress Disorder
Next Article in Special Issue
Divergence of Intracellular Trafficking of Sphingosine Kinase 1 and Sphingosine-1-Phosphate Receptor 3 in MCF-7 Breast Cancer Cells and MCF-7-Derived Stem Cell-Enriched Mammospheres
Previous Article in Journal
An Updated Review of Pro- and Anti-Inflammatory Properties of Plasma Lysophosphatidylcholines in the Vascular System
Previous Article in Special Issue
Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts
Article

Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism

1
Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany
2
Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
3
Department of Anaesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany
4
Department of Anaesthesiology and Intensive Care Medicine, Septomics Research Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany
5
Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
6
Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany
7
Institute of Anatomy and Cell Biology, University Medicine Greifswald, 17487 Greifswald, Germany
8
Department of Pediatrics, Klinikum Oldenburg, 26133 Oldenburg, Germany
9
Human Genetics, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany
10
Junior Research Group, Genetics of childhood brain malformations, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany
11
Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg,26129 Oldenburg, Germany
12
Centogene AG, D-18055 Rostock, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(12), 4502; https://doi.org/10.3390/ijms21124502
Received: 10 June 2020 / Revised: 19 June 2020 / Accepted: 21 June 2020 / Published: 24 June 2020
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
Niemann–Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions of Npc1−/− mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1−/− mice in all brain regions, together with distinct changes in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1−/− mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable. View Full-Text
Keywords: Niemann–Pick disease type C1; brain; fibroblasts; S1P; sphingosine-1-phosphate receptors; qRT-PCR; sphingolipids; HPTLC; mass spectrometry; white matter Niemann–Pick disease type C1; brain; fibroblasts; S1P; sphingosine-1-phosphate receptors; qRT-PCR; sphingolipids; HPTLC; mass spectrometry; white matter
Show Figures

Figure 1

MDPI and ACS Style

Gläser, A.; Hammerl, F.; Gräler, M.H.; Coldewey, S.M.; Völkner, C.; Frech, M.J.; Yang, F.; Luo, J.; Tönnies, E.; von Bohlen und Halbach, O.; Brandt, N.; Heimes, D.; Neßlauer, A.-M.; Korenke, G.C.; Owczarek-Lipska, M.; Neidhardt, J.; Rolfs, A.; Wree, A.; Witt, M.; Bräuer, A.U. Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism. Int. J. Mol. Sci. 2020, 21, 4502. https://doi.org/10.3390/ijms21124502

AMA Style

Gläser A, Hammerl F, Gräler MH, Coldewey SM, Völkner C, Frech MJ, Yang F, Luo J, Tönnies E, von Bohlen und Halbach O, Brandt N, Heimes D, Neßlauer A-M, Korenke GC, Owczarek-Lipska M, Neidhardt J, Rolfs A, Wree A, Witt M, Bräuer AU. Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism. International Journal of Molecular Sciences. 2020; 21(12):4502. https://doi.org/10.3390/ijms21124502

Chicago/Turabian Style

Gläser, Anne, Franziska Hammerl, Markus H. Gräler, Sina M. Coldewey, Christin Völkner, Moritz J. Frech, Fan Yang, Jiankai Luo, Eric Tönnies, Oliver von Bohlen und Halbach, Nicola Brandt, Diana Heimes, Anna-Maria Neßlauer, Georg C. Korenke, Marta Owczarek-Lipska, John Neidhardt, Arndt Rolfs, Andreas Wree, Martin Witt, and Anja U. Bräuer 2020. "Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism" International Journal of Molecular Sciences 21, no. 12: 4502. https://doi.org/10.3390/ijms21124502

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop